Gonadotropin Stimulation Reduces the Implantation and Live Birth Rate but Not the Miscarriage Rate of Embryos Transferred When Compared to Unstimulated In Vitro Fertilization.

Research suggests that gonadotropin stimulation in in vitro fertilization (IVF) treatment affects embryo quality and the endometrium that might influence embryo implantation, placentation and establishment of a viable pregnancy. We assessed the impact of gonadotropin stimulation on implantation, live birth and miscarriage rates per transferred embryo by comparing stimulated and unstimulated IVF treatment. In a cohort of 728 couples, 1310 IVF cycles with successful embryo transfer were analysed; 857 cycles were stimulated with gonadotropins > 75 IU/day (333 poor responder < 4 oocytes; 524 normal responders), and 453 were unstimulated. In total, 1913 fresh cleavage-stage embryos were transferred. Zygote but no embryo selection was performed, and supernumerous zygotes were vitrified. The implantation rate was defined as number of sonographically detected amniotic sacs; live birth rate as number of children born per transferred embryo. Modified mixed effect Poisson regression was used to account for the dependency of cycles and embryos within the same women and the same transfer cycle. Adjustments were made for maternal age, parity, primary or secondary infertility and indication for IVF. Per transferred embryo, implantation rates (rate ratio (RR) 1.37; 95% CI 1.04-1.81; p = 0.028; aRR 1.42; 95% CI 1.10-1.84; p = 0.008) and live birth rates (RR 1.33; 95% CI 0.95-1.86; p = 0.093; aRR 1.38; 95% CI 1.01-1.88; p = 0.044) were higher in NC-IVF compared to cIVF normal responders. Miscarriage did not differ (RR 0.99; 95% CI 0.59-1.65; p = 0.965; aRR 0.90; 95% CI 0.52-1.53 p = 0.698). Similar results were obtained in poor responders. The study suggests an impact of gonadotropin stimulation on the implantation potential of embryos.

Low-dose clomiphene citrate does not reduce implantation and live birth rates in otherwise unstimulated modified natural cycle IVF-retrospective cohort study.

RESEARCH QUESTION: Does antioestrogen effect of clomiphene citrate (CC) on the endometrium reduce implantation and thereby decrease pregnancy and live birth rate per transferred embryo? METHODS: In this cohort, unstimulated IVF cycles modified with clomiphene citrate (CC-NC-IVF) and unstimulated, natural IVF cycles (NC-IVF) conducted between 2011 and 2016 were included. CC was applied in a dosage of 25mcg per day, starting on cycle day 7 until ovulation trigger day. Primary outcomes were clinical pregnancy rate, defined as amniotic sac visible in ultrasound, and live birth rate per transferred embryo. Miscarriage rate calculated as amniotic sac not ending in a live birth was secondary outcome. A modified mixed-effect Poisson regression model was applied, and adjustments were made for female age, parity, type and cause of infertility. Additionally, stratification by parity and age was performed. RESULTS: Four hundred and ninety-nine couples underwent a total of 1042 IVF cycles, 453 being NC-IVF and 589 being CC-NC-IVF cycles. Baseline characteristics of both groups did not differ. Addition of CC did neither decrease clinical pregnancy rate (aRR 0.86; 95% CI 0.67-1.12) nor live birth rate per transferred embryo (aRR 0.84; 95% CI 0.62-1.13) in comparison with NC-IVF. Miscarriage rate did not differ between CC-NC-IVF and NC-IVF (aRR 0.95; 95% CI 0.57-1.57). CONCLUSION: Low-dose CC does not reduce pregnancy or live birth rate per transferred embryo. It can be used in infertility treatment without negatively affecting the endometrium and implantation.

COVID-19 Information-Seeking, Health Literacy, and Worry and Anxiety During the Early Stage of the Pandemic in Switzerland: A Cross-Sectional Study.

Objectives: To describe COVID-19 information-seeking behavior (CISB) during the first stage of the pandemic in Switzerland and identify its determinants. Methods: We conducted an online cross-sectional survey (4 May to 6 July 2020). Participants self-reported their CISB (information sources and frequency), personal COVID-19 situation (e.g., perception about having had COVID-19), sociodemographic information, and completed validated measures of health literacy, and worry and anxiety. Data were analyzed using descriptive statistics and logistic regressions. Results: We included 1,505 participants (24.7% male; mean age = 43.0 years, SD = 13.9). Most participants reported searching for information daily (n = 1,023, 68.0%) and referring to multiple information sources (mean 3.7, SD = 1.5). Commonly used sources were official websites (n = 1,129, 75.0%) and newspapers (n = 997, 66.2%). Participants with higher health literacy were more likely to seek information daily and use online resources, but less likely to use personal networks than those with lower health literacy. We did not find any association between CISB and worry and anxiety. Conclusion: More opportunities for personal dialogue and education about reliable online information resources should be encouraged to optimize the CISB of groups with lower health literacy.

Investigational medicinal products, related costs and hospital pharmacy services for investigator-initiated trials: A mixed-methods study.

BACKGROUND: Conducting high quality investigator-initiated trials (IITs) is challenging and costly. The costs of investigational medicinal products (IMPs) in IITs and the role of hospital pharmacies in the planning of IITs are unclear. We conducted a mixed-methods study to compare planned and actual costs of IMPs in Swiss IITs, to examine potential reasons for differences, and to gather stakeholder views about hospital services for IITs. METHODS: We included all IITs with IMP services from the Basel hospital pharmacy invoiced between January 2014 and June 2020 (n = 24). We documented trial and IMP characteristics including planned and actual IMP costs. Our working definition for a substantial cost difference was that the actual IMP costs were more than 10% higher than the planned IMP costs in a trial. We conducted semi-structured interviews with investigators, clinical trials unit and hospital pharmacy staff, and qualitatively analyzed transcribed interviews. RESULTS: For 13 IITs we observed no differences between planned and actual costs of IMPs (median, 11'000 US$; interquartile range [IQR], 8'882-16'302 US$), but for 11 IITs we found cost increases from a median of 11'000 US$ (IQR, 8'922-36'166 US$) to a median over 28'000 US$ (IQR, 13'004-49'777 US$). All multicenter trials and 10 of 11 IITs with patients experienced substantial cost differences. From the interviews we identified four main themes: 1) Patient recruitment and organizational problems were identified as main reasons for cost differences, 2) higher actual IMP costs were bearable for most investigators, 3) IMP services for IITs were not a priority for the hospital pharmacy, and 4) closer collaboration between clinical trial unit and hospital pharmacy staff, and sufficient staff for IITs at the hospital pharmacy could improve IMP services. CONCLUSIONS: Multicenter IITs enrolling patients are particularly at risk for higher IMP costs than planned. These trials are more difficult to plan and logistically challenging, which leads to delays and expiring IMP shelf-lives. IMP services of hospital pharmacies are important for IITs in Switzerland, but need to be further developed.

Perinatal outcomes in singletons after fresh IVF/ICSI: results of two cohorts and the birth registry.

RESEARCH QUESTION: How are perinatal outcomes of live-born singletons after stimulated and unstimulated IVF different from perinatal outcomes in (i) children born in a tertiary centre and (ii) all children born in Switzerland? METHODS: This cohort study compared the perinatal outcomes of two birth cohorts and the national live birth registry. Relative risks were calculated using modified Poisson regression and clustering for siblings and adjustment for maternal age, parity and childs sex. RESULTS: Of the 636,639 live births, 311 were in the Bern IVF Cohort (144 stimulated, 167 unstimulated), 2332 in the tertiary centre and 633,996 in the Swiss Live Birth Registry (SLBR). Perinatal outcomes following IVF did not differ compared with births in the SLBR (adjusted relative risk [aRR]; 95% confidence interval [CI]), with the exception of the increased risk of small for gestational age (1.31; 1.01 to 1.70, P = 0.04; aRR 1.12; 0.87 to 1.45, P = 0.39). Children born following stimulated IVF had a higher risk of low birthweight (2.17; 1.27 to 3.69, P < 0.01; aRR 1.72; 1.01 to 2.93, P = 0.05), and of being small for gestational age (1.50; 1.05 to 2.14, P = 0.03; aRR 1.31; 0.92 to 1.87; P = 0.13), whereas children born after unstimulated IVF had no increased risks compared with the SLBR. Higher Caesarean rate after IVF was mainly associated with higher maternal age. CONCLUSION: Singletons in the Bern IVF Cohort do not show less favourable perinatal outcomes. Gonadotrophin stimulation seems to have an effect, because lower risks were associated with unstimulated IVF.

The endocrine milieu in naturally matured follicles is different in women with high serum anti-Müllerian hormone concentrations.

RESEARCH QUESTION: Is the endocrine milieu different in women with low serum anti-Müllerian hormone (AMH) concentration compared with women with high concentration? DESIGN: Cohort study of 84 women (four groups) classified according to AMH concentration and age undergoing natural cycle IVF treatment. Concentrations of LH, oestradiol, testosterone, androstenedione and AMH were determined in follicular fluid (FF), associations analysed and clinical outcome parameters evaluated. RESULTS: A positive correlation between serum and FF AMH concentrations was confirmed. Follicular fluid androstenedione concentration was positively correlated with serum AMH concentration (P < 0.0001, r2 = 0.197). The correlation between FF LH and FF testosterone concentration in all women was not significant (P = 0.050, r2 = 0.046); however, the correlation between FF androstenedione in women with high serum AMH concentration was significant (P = 0.032, r2 = 0.220). Follicular fluid testosterone and androstenedione were positively correlated with FF oestradiol overall and in some individual groups. The high serum AMH concentration group showed the highest FF AMH and androstenedione concentrations and lowest oestradiol-testosterone and oestradiol-androstenedione ratios. High FF AMH concentration was associated with a higher clinical pregnancy rate and high FF oestradiol concentration with a slightly better embryo quality. CONCLUSIONS: Differences in the endocrine milieu in women with high serum AMH concentration seem to be caused by increased follicular LH concentration. In women with high serum AMH concentration, FF androstenedione is increased and ratios of oestradiol-testosterone and oestradiol-androstenedione are decreased, suggesting a disturbed endocrine milieu caused by reduced metabolization of FF androgens into oestrogens. In natural cycles, FF AMH concentrations are positively associated with higher clinical pregnancy rates and oestradiol concentrations with a higher embryo score.

Breastfeeding following in vitro fertilisation in Switzerland-Does mode of conception affect breastfeeding behaviour?

AIM: Breastfeeding has numerous advantages. Our aim was to investigate whether breastfeeding initiation and duration in women with pregnancies conceived through in vitro fertilisation differ from spontaneously conceived pregnancies. METHODS: This is a comparative cross-sectional study about breastfeeding behaviour performed at the Bern University Hospital including mothers of singletons conceived by in vitro fertilisation (n = 198) with or without gonadotropin stimulation between 2010 and 2016 (in vitro fertilisation group). They were compared to a population-based control group (n = 1421) of a randomly selected sample of mothers in Switzerland who delivered in 2014. RESULTS: A total of 1619 women were included in this analysis. Breastfeeding initiation rates were high, similar between the in vitro fertilisation group (93.4%) and the control group (94.8%). No increased risk of stopping breastfeeding earlier after in vitro fertilisation treatment compared to the control group could be found over the observational period of 12 months (HR = 1.00, 95% CI 0.83-1.20, P = .984). There was no difference in breastfeeding initiation or duration after gonadotropin-stimulated vs unstimulated in vitro fertilisation. CONCLUSION: In Switzerland, in vitro fertilisation treatments were not associated with earlier breastfeeding cessation. This result is reassuring for mothers undergoing in vitro fertilisation.

Euphrasia Eye Drops in Preterm Neonates With Ocular Discharge: A Randomized Double-Blind Placebo-Controlled Trial.

Aim: To investigate whether the early administration of Euphrasia eye drops® in preterm neonates presenting with ocular discharge fosters the resolution of the ocular discharge and reduces the need for topical antibiotic therapy, as compared to placebo. Methods: We conducted a randomized double-blind placebo-controlled trial at the University Children's Hospital Bern, Switzerland. Preterm neonates with white, yellow, or green ocular discharge were included. Infants were randomly assigned (1:1) to the Euphrasia arm (Euphrasia eye drops®, Weleda AG, Arlesheim) or the placebo arm (NaCl 0.9%). Euphrasia or placebo was administrated at a dose of one drop in each eye four times a day over a period of 96 h. The primary outcome was the treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. Results: A total of 114 neonates were screened and 84 were randomized. Among neonates in the Euphrasia arm, 22 (55.0%) achieved our primary outcome compared to 21 (51.2%) in the placebo arm (p = 0.85). In the Euphrasia arm, time to resolution of reddening tended to fall within the shorter bracket of 24 to 48 h (24 (92.3%) vs. 12 (80.0%) in the placebo arm, p = 0.34) and relapse or first signs of reddening during the 96-h intervention tended to be lower [3 (7.9%) eyes vs. 8 (18.2%) eyes in the placebo arm, p = 0.17]. Tearing at 96 h tended to be lower in the Euphrasia arm [5 (12.8%) eyes in the Euphrasia arm vs. 12 (27.3%) eyes in the placebo arm, p = 0.10]. Discussion: Euphrasia did not significantly improve treatment success, defined as no ocular discharge at 96 h and no use of topical antibiotic therapy during the 96-h intervention. However, results suggest that Euphrasia may be of benefit for symptoms such as reddening and tearing, and thus improve the comfort of patients. Trial Registration: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov) NCT04122300 and at the portal for human research in Switzerland SNCTP000003490.